title: Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model.
abstract: The pathological end-state of Parkinson disease is well described from postmortem tissue, but there remains a pressing need to define early functional changes to susceptible neurons and circuits. In particular, mechanisms underlying the vulnerability of the dopamine neurons of the substantia nigra pars compacta (SNc) and the importance of protein aggregation in driving the disease process remain to be determined. To better understand the sequence of events occurring in familial and sporadic Parkinson disease, we generated bacterial artificial chromosome transgenic mice (SNCA-OVX) that express wild-type α-synuclein from the complete human SNCA locus at disease-relevant levels and display a transgene expression profile that recapitulates that of endogenous α-synuclein. SNCA-OVX mice display age-dependent loss of nigrostriatal dopamine neurons and motor impairments characteristic of Parkinson disease. This phenotype is preceded by early deficits in dopamine release from terminals in the dorsal, but not ventral, striatum. Such neurotransmission deficits are not seen at either noradrenergic or serotoninergic terminals. Dopamine release deficits are associated with an altered distribution of vesicles in dopaminergic axons in the dorsal striatum. Aged SNCA-OVX mice exhibit reduced firing of SNc dopamine neurons in vivo measured by juxtacellular recording of neurochemically identified neurons. These progressive changes in vulnerable SNc neurons were observed independently of overt protein aggregation, suggesting neurophysiological changes precede, and are not driven by, aggregate formation. This longitudinal phenotyping strategy in SNCA-OVX mice thus provides insights into the region-specific neuronal disturbances preceding and accompanying Parkinson disease.
authors.affiliation: Oxford Parkinson's Disease Centre Department of Physiology, Anatomy and Genetics, Medical Research Council Anatomical Neuropharmacology Unit, Department of Pharmacology, Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, and Department of Experimental Psychology, University of Oxford, Oxford OX1 3QX, United Kingdom.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Janezic
authors.forename: Sarah
authors.initials: S
authors.lastname: Threlfell
authors.forename: Paul D
authors.initials: PD
authors.lastname: Dodson
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Dowie
authors.forename: Tonya N
authors.initials: TN
authors.lastname: Taylor
authors.forename: Dawid
authors.initials: D
authors.lastname: Potgieter
authors.forename: Laura
authors.initials: L
authors.lastname: Parkkinen
authors.forename: Steven L
authors.initials: SL
authors.lastname: Senior
authors.forename: Sabina
authors.initials: S
authors.lastname: Anwar
authors.forename: Brent
authors.initials: B
authors.lastname: Ryan
authors.forename: Thierry
authors.initials: T
authors.lastname: Deltheil
authors.forename: Polina
authors.initials: P
authors.lastname: Kosillo
authors.forename: Milena
authors.initials: M
authors.lastname: Cioroch
authors.forename: Katharina
authors.initials: K
authors.lastname: Wagner
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
authors.forename: David M
authors.initials: DM
authors.lastname: Bannerman
authors.forename: J Paul
authors.initials: JP
authors.lastname: Bolam
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Magill
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Cragg
authors.forename: Richard
authors.initials: R
authors.lastname: Wade-Martins
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009435:Synaptic Transmission; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000235:genetics
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein
keywords: behavioral phenotyping; dopamine transmission; in vivo electrophysiology; neurodegeneration; voltammetry